Hydrocodone and hydromorphone are semi-synthetic opioids. Hydrocodone (a synonym for dihydrocodeinone) is a codeine derivative whereas hydromorphone (a synonym for dihydromorphinone) is a morphine derivative. Historically, hydrocodone, commonly as a bitartrate salt, has been used orally as an antitussive or as a narcotic analgesic for treating moderate to severe pain, often in combination with paracetamol (acetaminophen) or ibuprofen. It is approximately 1.5 times less potent an opioid than oxycodone. In the United States, hydrocodone, by itself, is a Schedule II drug. Until recently, the only commercial hydrocodone products approved by the U.S. Food and Drug Administration (USFDA) were combined with another medication, which is often a painkiller and is most frequently acetaminophen. These medications, which are classified as Schedule III products, include Anexsia®, Lortab®, Norco® and Zydone®. The rationale of combining hydrocodone with other painkillers is that the combination may increase efficacy and the adverse effects may be reduced as compared with an equally effective dose of a single active agent. Recently, several pharmaceutical companies have been developing extended-release formulations of hydrocodone by itself and, in October 2013, USFDA approved Zohydro™ ER (Zogenix Inc.) which may avoid the issue of hepatotoxicity of acetaminophen containing formulations.
Hydromorphone, commonly as a hydrochloride salt, is also a potent analgesic drug of the opioid class. Like hydrocodone, hydromorphone is also used as an antitussive for cases of dry, painful coughing. Hydromorphone is commonly used in hospital settings, mostly intravenously (IV) because its bioavailability orally, rectally, and intranasally is very low. Sublingual administration is usually superior to swallowing for bioavailability and effects. Hydromorphone is significantly more potent and much more soluble in water than morphine and therefore hydromorphone solutions can be produced to deliver the drug in a smaller volume of water. Hydromorphone is known by various brand names around the world including Dilaudid™, Hydal™, Dimorphone™, Sophidone™, Hydrostat™, Hydromorfan™, Hydromorphan™, Hymorphan™, Laudicon™ and Opidol™.
An extended-release version of hydromorphone called Palladone™ was available for a short time in the United States before being voluntarily withdrawn from the market after a July 2005 USFDA advisory warned of a high overdose potential when taken with alcohol. There is, however, a newer extended-release (once-daily) version of hydromorphone, approved by USFDA in March 2010 and now available in the United States, marketed under the brand name Exalgo® (Mallinckrodt Inc.). It has been reported that Exalgo® does not have the same “dose dumping” issue as Palladone™. An identical once-daily formulation has been launched in several countries under the trade name Jurnista® (Janssen-Cilag). Exalgo® and Jurnista® both employ the Oros® Push-Pull™ osmotic delivery system designed to release hydromorphone at a controlled rate over an extended period of time allowing for once-daily administration. Like hydrocodone, and the other opioids used for analgesia, hydromorphone is classified as a Schedule II drug in the United States.
Conventional processes for making hydrocodone and hydromorphone involve the use of codeine and morphine, respectively, as starting materials and oxidation/reduction steps. However, these processes are generally considered to be more expensive and less efficient than known “diimide” routes to making hydrocodone and hydromorphone from thebaine and oripavine, respectively.
A process for preparing hydrocodone from thebaine by reducing thebaine to 8,14-dihydrothebaine with diimide, followed by hydrolysis of the 8,14-dihydrothebaine to hydrocodone, is described in U.S. Pat. Nos. 3,812,132 and 8,399,671 (incorporated herein by reference in their entirety). Similarly, a process for preparing hydromorphone from oripavine by reducing the oripavine to 8,14-dihydroripavine with diimide, followed by hydrolysis of the 8,14-dihydroripavine to hydromorphone is also described in U.S. Pat. No. 8,399,671 as well as U.S. Pat. Appl. Publ. No. 2006/0009479.
These known processes provide for the formation of diimide in situ by heating a sulfonic acid hydrazide, such as p-toluenesulfonyl hydrazide, in an organic solvent, with or without the presence of a base such as an alkali metal hydroxide or an organic base such as ethanolamine or morpholine.
Contacting the heated sulfonic acid hydrazide and solvent with a thebaine or oripavine solution results in the evolution of gases, such as nitrogen, that are bi-products of the processes. The potential exists for these gases to increase in volume and pressure, and therefore can pose safety issues especially when the hydrazide is added rapidly to the thebaine and oripavine solutions. Additionally, isolation of the 8,14-dihydrothebaine or 8,14-dihydroripavine products typically involves a tedious solvent distillation at the end of the reaction, followed by the addition of water and basification. The distillation process can result in product impurities either from the residual hydrazide reagent or from degradation of by-products of the process.
As with other pharmaceutical processes, it is desirable to attain improvements especially with respect to process safety and product impurities. In particular, there is a continuing need in the art to provide improved processes for making hydrocodone and hydromorphone alkaloids. We have discovered improved processes for making hydrocodone and hydromorphone as well as their derivatives 8,14-dihydrothebaine and 8,14-dihydrooripavine.
All references cited herein are incorporated by reference in their entireties for all purposes.